9alpha, 11alpha-epoxy and 11beta-chloro-9alpha-hydroxy 17alpha-(2-carboxyethyl)-17beta-hydroxyandrost-4-en-3-one gamma-lactones and delta1 and delta6 analogs



United States Patent This invention relates to 9a,1la-epoxy and 11fi-halo- 9a-hydroxy 17a-(2 carboxyethyl)-17fi+hydroxyandrost-4- en-3-one 'y-lactones and the A and A analogs thereof, as also processes whereby these products can be prepared. More particularly, this invention relates to new and useful pure chemical compounds having, in the case of the epoxides, the formula in which formulas Z and Z" each represents an ethylene or vinylene radical and X represents halogen, especially chlorine.

Equivalent to the foregoing lactones for the purposes of this invention are the corresponding hydroxy acids and their alkali salts of the formulas represents hydrogen, an alkali metal, or the ammonium radical.

The compounds to which this invention relates are usein] because of their valuable pharmacological properties.

Thus, for example, they block the effect of desoxycorticosterone acetate on urinary sodium and potassium. This effect is especially unexpected in the epoxy compounds comprehended, since isomers thereof represented by 170:- (2 carboxye-thyl)-95,l1B-epoxy-l7p-hydroxyandrost-4- en-3-one -lactone are relatively inactive as desoxycorticosterone acetate blockers under substantially identical conditions of test. I

Preparation of the instant lactones proceeds from the 170: -(2 carboxyethyl)-17/3-hydroxyandrosta-4-9( l1)- dien-3-one 'y-lactones LII which, upon oxidation with perbenzoic acid in anhydrous benzene, afford the corresponding epoxy compounds hereof the latter compounds, in turn, being converted on contact with concentrated hydrohalic acid in dichloromethane to the claimed halohydrins Z, Z", and X in the formulas retaining the meanings previously assigned.

Those skilled in the art will appreciate that the salts set forth readily devolve from the apposite lactones on contact with aqueous alkali, and the free acids are obtained from the salts by a critically brief exposure to a proton source. Prolongation of the epoxsure time induces lactoniza-t-ion.

The following examples describe in detail compounds illustrative of the present invention and methods whereby these compounds can be prepared. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic chemistry that many modifications, both of materials and of methods, may be practiced without departing from the purpose and intent of this dis- 3 EXAMPLE 1 17a-(2-carboxyethyl)-9a,11o: epoxy 17,3 hydroxyandrst-4-en-3-one 'y-lact0ne.-To a solution of 27 parts of 17a-(2-carboxyethyl)-17fl-hydroxyandrosta-4,9 1 l) -diene- 3-one 'y-lactonepreparable as described in US. 2,925,- 416in 450 parts of anhydrous benzene is added a solution of approximately 17 parts of perbenzoic acid in 180 parts of anhydrous benzene, temperatures of the order of 5 being maintained throughout the addition and for 24 hours thereafter. The reaction mixture is then allowed to stand at room temperatures for 48 hours, whereupon 460 parts of hexane is introduced and the resultant mixture chilled to induce crystallization. The crystals thrown down are filtered off and recrystallized from acetone to afford colorless 17u-(2-carboxyethyl)- 9a,l1a-epoxy-l7/3-hydroxyandrost-4-en-3 one 'ylactone melting at 258-262 with decomposition. The product has the formula EXAMPLE 2 17a-(2-carboxyethyl) -11;8-chl0ro-9a-I7B dihydroxyandr0st-4-en-3-0ne 'y-lact0ne.To a solution of 1 part of l7u-( 2carboxyethyl)-9a, l l u-epoxy-l7 18 hydroxyandrost- 4-en-3-one v-lactone in 80 parts of dichloromethane is added 71 parts of concentrated hydrochloric acid. The resultant biphasic mixture is maintained with vigorous agitation at room temperatures for 15 minutes, whereupon it is allowed to layer out and the lower layer is separated, suc cessively washed with water, aqueous 2% potassium bicarbonate, and water. The solution thus obtained is dried over anhydrous sodium sulfate and stripped of solvent by distillation, afiording as the residue l7a-(2-carboxyethyl)- 1lB-chloro-9a,l7 3-dihydroxyandrost-4-en-3-one 'y-lactone which, upon recrystallization from ethyl acetate, melts at 187l90 with decomposition. The product has the formula EXAMPLE 3 (A) 1 7a- (2-carboxyethyl 7B-hydr0xyandr0sta-1 ,4,9

(B) 1 7a-(2-carb0xyethyl)-9a,11a-ep0xy-17fl-hydr0xyandrosta-1,4-dien-3-one 'y-lact0ne.-A solution of 10 parts of l7a-(2-carboxyethyl)-l7B-hydroxyandrosta-l,4,9(11)- trien-3-one y-lactone and 6 parts of perbenzoic acid in 240 parts of anhydrous benzene is maintained at 5 for 96 hours and then let stand at room temperatures for 24 hours. Approximately 244 parts of hexane is thereupon added, inducing crystallization. The crystals are filtered 01f, washed with hexane, and successively recrystallized from ethyl acetate and a mixture of acetone and hexane to give 17 8-(2-carboxyethy1)-9u,11a-epoxy-17fihydroxyandrosta-l,4-dien-3-one 'y-lactone melting at 250- 255 with decomposition. The product has the formula EXAMPLE 4 17a-(Z-carboxyethyl)-11fl-chloro-9a,17fl dihydroxyandrosta-L4-dien-3-one 'y-lactone.To a solution of 3 parts of 17oc-(2-carboxyethyl)-9a,llea-epoxy l7fl hydroxyandrosta-l,4-d-ien-3-one 'y-lactone in 268 parts of dichloromethane is added 240 parts of concentrated hydrochloric acid. The resultant biphasic mixture is maintained with vigorous agitation at room temperatures for 15 minutes (11)-trien-3-one 'ylact0ne.A mixture of 10 parts of l7oc- (Z-carboxyethyl) l7fi-hydroxyandrosta-4,9 l l -dien- 3-one -lactone, approximately 8 parts of 2,3-dichloro-5,6- dicyanobenzoquinone, and 225 parts of anhydrous benzene is maintained at the boiling point under reflux with agitation for 24 hours. It is then cooled to room temperature and filtered. The filtrate is diluted with approximately 70 parts of ether and washed with 400 parts of aqueous 2% sodium sulfite. It is then filtered through diatomaceous earth, washed well with water, dried over anhydrous sodium sulfate, and freed of solvent by distillation. The residue, crystallized from methanol, affords 'l7a-(2-carboxyethyl) -l7fl-hydroxy-androsta-1,4,9 l l -trien-3-one 'y-lactone melting at 86-90.

and then let stand to layer out. The lower layer is separated; successively washed with water, aqueous 2% potassium bicarbonate, and water; dried over anhydrous sodium sulfate; and stripped of solvent by distillation. Addition of approximately 20 parts of methanol to the residue causes it to solidify. The solid material, twice recrystallized from ethyl acetate, affords 17a-(2-carboxyethyl)-11B- chloro-9a,l7fi-dihydroxyandrosta-l,4-dien-3-one -lactone melting at approximately 205-206" with decomposition. The product has the formula EXAMPLE 5 (A) 17oz (2 carboxyethyl) 1719 hydroxyandrosta- 4,6,9(11)-trien-3-0ne 'ylactone.-A mixture of 2 parts of 17a (2 carboxyethyl) 17p hydroxyandrosta 4,9 (11)-dien-3-one 'y-lactone, 4 parts of chloranil, and 112 parts of tert-butyl alcohol is heated at the boiling point under reflux with agitation for 5 hours. It is then cooled to room temperature and filtered. The filtrate is freed of solvent by distillation, and the oily residue is taken up in chloroform. The chloroform solution is consecutively washed with water, aqueous 5% sodium bicarbonate, and water. It is then dried over anhydrous sodium sulfate and freed of solvent by distillation, leaving an oil which is chromatographed on silica gel, using benzene and ethyl acetate as developing solvents. From an eluate comprising 10% ethyl acetate in benzene is obtained, upon evaporation of solvent, pure l7a-(2-carboxyethyl)-l7fi-hydroxyandrosta-4,6,9( l1)-trien-3-one 'y-lactone as an oil.

(B) (2 carboxyethyl) 9a,l1a epoxy 17,6 hydrox-yandr0sta-4,6-dien-3-0ne 7-lact0ne.-A solution of 20 parts of 17a-(2-carboxyethyl)-1713-hydroxyandrosta-4, 6,9(11)-trien-3-one 'y-lactone and 13 parts of perbenzoic acid in 515 parts of anhydrous benzene is maintained at for 72 hours and then let stand at room temperatures for 24 hours. The resultant mixture is filtered, and the filtrate is diluted with 320 parts of hexane. Precipitation occurs. The precipitate, collected on a filter and twice recrystallized from acetone, affords 17u(2-carboxyethyl)- 906,110; epoxy 175 hydroxyandrosta 4,6 dien 3- one 'y-lactone melting at approximately 305 with decomposition. The product has the formula What is claimed is:

1. A compound selected from the group consisting of 9u,11a-epoxides of the formula and corresponding halohydrins of the formula in which formulas one of Z and Z" designates an ethylene radical and the other designates a member of the group consisting of ethylene and vinylene radicals.

2. 17a (2 carboxyethyl) 911,110 epoxy 17,8 hydroxyandrost-4-en-3-one -y-lactone.

3. 17a (2 carboxyethyl) llfi chloro 901,175 dihydroxyandrost-4-en-3-one 'y-lactone.

4. 17a (2 carboxyethyl) 911,110: epoxy 17,8 hydnoxyandrosta-l ,4-dien-3 -one, 'y-lactone.

-5. 17a (2 carboxyethyl) llfl chloro 911,175 dihydroxyandrosta-l,4-dien-3-one 'y-lactone.

6. 17a (2 carboxyethyl) 9a,11a epoxy 17p hydroxyandrosta-4,6-dien-3-one q-lactone.

Chemical & Engineering News, vol. 37, No. 16, April 20, 1959, page 40. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 9A,11A-EPOXIDES OF THE FORMULA 